The Risk for Bleeding in Patients With Atrial Fibrillation From Concomitant Use of Apixaban or Rivaroxaban With Diltiazem Compared With Metoprolol

BACKGROUND: Diltiazem is a potent inhibitor of cytochrome P450 3A4 and P-glycoprotein substrates, which can affect the metabolic pathways of factor Xa inhibitors, predisposing patients with atrial fibrillation (AF) to serious bleeding complications. OBJECTIVE: To compare the risk for bleeding among patients with AF who used apixaban or rivaroxaban in combination with diltiazem compared with metoprolol. DESIGN: Retrospective cohort active comparator study. SETTING: U.S. administrative health care database. PATIENTS: Persons with AF. INTERVENTION: Use of apixaban or rivaroxaban with diltiazem or metoprolol. MEASUREMENTS: The primary study outcome was a composite of serious bleeding events leading to hospitalization. Secondary study outcomes included composites of stroke or systemic embolism. Diltiazem was stratified by high dose (>120 mg/d) and low dose (≤120 mg/d). Propensity score matching was used to adjust for differences between diltiazem and metoprolol users. RESULTS: In the matched cohort of patients with AF, 23 000 were users of diltiazem and 23 000 were users of metoprolol. After propensity score matching, diltiazem (vs. metoprolol) was associated with a higher risk for bleeding events (rate difference [RD], 5.4 [95% CI, 1.2 to 9.6] per 1000 person-years). The risk for bleeding increased with high- versus low-dose diltiazem (high dose: RD, 9.2 [CI, 2.7 to 15.7]; low dose: RD, 2.6 [CI, 0.5 to 8.0]). The estimated 12- and 6-month risk differences between diltiazem and metoprolol were 0.48 percentage points (CI, 0.09 to 0.83 percentage points) and 0.31 percentage points (CI, 0.04 to 0.58 percentage points), respectively. LIMITATION: Residual confounding. CONCLUSION: In commercially insured patients with AF receiving apixaban or rivaroxaban, the use of diltiazem was associated with an increased risk for serious bleeding complications when compared with metoprolol. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.